Inhibition of drug metabolism by hydroxylated metabolites: cross-inhibition and specificity.

Inhibition of drug metabolism was studied in adult male Sprague-Dawley rats. A hydroxylated metabolite of phenylbutazone (oxyphenbutazone) inhibited the elimination of phenytoin, which is metabolized by oxidative pathways. The biotransformation of a relatively polar and only slightly plasma protein-bound drug, antipyrine, was subject to product inhibition by a hydroxylated metabolite, 4-hydroxyantipyrine. Neither oxyphenbutazone nor 4-hydroxyantipyrine measurably affected the elimination kinetics or metabolic fate of a drug (sulfanilamide) that is not metabolized by oxidative pathways.